S177: EVALUATING SERUM FREE LIGHT CHAIN RATIO AS A BIOMARKER FOR MULTIPLE MYELOMA
Authors: T. Akhlaghi, K. Maclachlan, N. Korde, S. Mailankody, A. Lesokhin, H. Hassoun, S. X. Lu, D. Patel, U. Shah, C. Tan, A. Derkach, O. Lahoud, H. J. Landau, G. L. Shah, M. Scordo, D. J. Chung, S. A. Giralt, S. Z. Usmani, O. Landgren, M. Hultcrantz
Journal: HemaSphere (2022)

Background: In 2014, the definition of multiple myeloma (MM) was updated to include serum free light chain (FLC) ratio ≥100 as a myeloma defining biomarker, based on retrospective data indicating a 2-year progression rate of 80% and a median time to progression (TTP) of 12 months associated with this marker. As a result, patients previously diagnosed as smoldering MM (SMM), were considered to have MM requiring treatment if they had a FLC ratio ≥100. However, two recent studies have reported lower 2-year progression rates, 30-44%, and a longer median TTP of 40 months in patients with FLC ratio ≥100, raising concern about the FLC criteria. Aims: To assess the risk of progression in patients with SMM and a FLC ratio ≥100. Methods: We performed a retrospective analysis of patients diagnosed with SMM at Memorial Sloan Kettering Cancer Center between January 2000 and December 2017. Diagnosis of SMM and progression to active MM requiring therapy was defined according to the International Myeloma Working Group (IMWG) criteria at the time of diagnosis. Kaplan-Meier method was used to assess TTP and generate survival curves, with log-rank test for comparison between groups. Results: A total of 438 patients were included in the study, with a median follow-up time of 52 months. While all patients with FLC ≥100 (n=66) had elevated involved FLC levels, 35 (53%) had an involved FLC concentration >100 mg/L. Per current diagnostic criteria, we only included patients with an involved FLC concentration >100 mg/L in the FLC ratio ≥100 group and found a median TTP of 31 months (95% confidence interval [CI] 16-59 months) and a 2-year progression rate of 49% (CI 28-63%). In a sensitivity analysis including all 66 cases with FLC ratio ≥100 (independent of involved FLC concentration), we found the median TTP to be 41 months (CI 30-72 months), compared to 101 months for those with a FLC ratio <100 (CI 78-127 months; p<0.0001). Furthermore, the risk of progression within 2 years was 35% (CI 22-46%) compared to 18% (CI 14-23%; p<0.0001) for those with a FLC ratio <100. Of note, 22 patients with a FLC ratio ≥100 were monitored expectantly for >4 years, among whom 12 patients had involved FLC levels >100 mg/L. Ten patients (7 with involved FLC level >100 mg/L) were followed over a period ranging from 4 to 8.5 years before eventually progressing, and 12 patients (5 with an involved FLC level >100 mg/L) were followed between 4 and 8 years and did not progress during the study period. Image:Summary/Conclusion: While FLC ratio ≥100 is associated with a high risk of progression in patients with SMM, it does not infer an imminent risk of progression, defined by the IMWG as median TTP of 12 months and 2-year progression rate of at least 80%. On the contrary, select patients with FLC ratio ≥100 can be followed for many years without progressing and some may never progress despite long-term follow-up. These findings suggest that in patients where FLC ratio ≥100 is the only myeloma-defining event, other high-risk features as well as the evolution of FLCs over time should be considered in the decision to start a patient on treatment.